Lorcaserin and : emerging selectivity of subtype–targeted

Herbert Y. Meltzer, Bryan L. Roth

J Clin Invest. 2013;123(12):4986-4991. https://doi.org/10.1172/JCI70678.

Review

Serotonin (5-hydroxytryptamine, or 5-HT) receptors mediate a plethora of physiological phenomena in the brain and the periphery. Additionally, dysfunction has been implicated in nearly every neuropsychiatric disorder. The effects of serotonin are mediated by fourteen GPCRs. Both the therapeutic actions and side effects of commonly prescribed drugs are frequently due to nonspecific actions on various 5-HT receptor subtypes. For more than 20 years, the search for clinically efficacious drugs that selectively target 5-HT receptor subtypes has been only occasionally successful. This review provides an overview of 5-HT receptor pharmacology and discusses two recent 5-HT receptor subtype–selective drugs, and pimavanserin, which target the 5HT2C and 5HT2A receptors and provide new treatments for and Parkinson’s disease , respectively.

Find the latest version: https://jci.me/70678/pdf Review Lorcaserin and pimavanserin: emerging selectivity of serotonin receptor subtype–targeted drugs Herbert Y. Meltzer1 and Bryan L. Roth2

1Department of Psychiatry and Behavioral Sciences, Northwestern Feinberg School of Medicine, Chicago, Illinois, USA. 2Department of Pharmacology, University of North Carolina Chapel Hill Medical School, Chapel Hill, North Carolina, USA.

Serotonin (5-hydroxytryptamine, or 5-HT) receptors mediate a plethora of physiological phenomena in the brain and the periphery. Additionally, serotonergic dysfunction has been implicated in nearly every neuropsychiatric disorder. The effects of serotonin are mediated by fourteen GPCRs. Both the therapeutic actions and side effects of commonly prescribed drugs are frequently due to nonspecific actions on various 5-HT receptor subtypes. For more than 20 years, the search for clinically efficacious drugs that selectively target 5-HT receptor subtypes has been only occasionally successful. This review provides an overview of 5-HT receptor pharmacology and discusses two recent 5-HT receptor subtype–selective drugs, lorcaserin and pimavanserin, which target the 5HT2C and 5HT2A receptors and provide new treatments for obesity and Parkinson’s disease psychosis, respectively.

Serotonin receptors and signal transduction 5-HT1 family of receptors has been successfully exploited for the Serotonin, which was known to be the principal vasoconstricting treatment of and depression with the development of substance found in serum, was chemically identified as 5-hydroxy- drugs like (Table 1), which is a selective 5-HT1A partial by Rapport and colleagues in 1948 (1). Although the . Likewise, 5-HT1B and 5-HT1D receptors represent canoni- effects of serotonin on smooth muscle and other peripheral organs cal targets for antimigraine including various ergots were long appreciated, it wasn’t until its structural similarity to (e.g., , , and ) as well diethylamide (LSD) was noted that serotonin and its as the more selective tryptans (e.g., sumatryptan and analogs) receptors were linked to (2). Distinct seroto- (18, 19). No selective 5-HT1E drugs exist and though selective nin receptor subtypes were proposed in 1957 (3), with the 5-HT1 5-HT1F drugs have been developed, none of them have yet been receptors having high affinity for serotonin and the 5-HT2 recep- approved by the FDA (Table 1). Theoretically, 5-HT1F antagonists tors having relatively low affinity for 5-HT. The so-called 5-HT1 might represent novel therapeutic agents for migraine . and 5-HT2 receptors identified pharmacologically by Gaddum The 5-HT2 family receptors couple to Gq G proteins and modu- and colleagues (3) roughly correspond to what are now known as late phosphoinositide hydrolysis and PKC activation (20–22). 5-HT2 the 5-HT1 and 5-HT2 families of receptors (Figure 1). family receptors typically have lower affinity for molecular seroto- With the development of radioligand-binding technology, mul- nin than other 5-HT receptors and are often potently inhibited by tiple distinct serotonin receptors were identified based principally both typical (12) and atypical (23) drugs (24). 5-HT2A on their differential radioligand-binding properties. Following the receptors represent the main serotonin receptors found in platelets, cloning of the β- receptor (4), 5-HT1A (5), the first so- vascular smooth muscle, and the (25, 26). As dis- called orphan GPCR, was cloned by Brian Kobilka in collaboration cussed below, 5-HT2B receptors are enriched in the (27), and with Marc Caron and others (6, 7). In rapid succession, the large drugs likely mediate their valvulopathogenic actions on heart valves family of G protein–coupled serotonin receptors we now appreci- via a combination of G protein and β-arrestin signaling (27–29). The ate were identified by molecular cloning technology and charac- distribution and function of 5-HT2C receptors will be summarized terized by pharmacological and biochemical studies (8, 9), includ- below when lorcaserin, a selective 5-HT2C agonist, is discussed. ing 5-HT1B/1D (10) and 5-HT1E (11), as well as 5-HT2A (12, 13) and The 5-HT4, 5-HT6, and 5-HT7 families of receptors are all cou- 5-HT2C (14, 15), which have lower affinities for 5-HT than the other pled to the Gs G proteins and mediate the stimulatory effects of serotonin receptors. The 5-HT4 receptor was also one of the early serotonin on cAMP accumulation. 5-HT4 receptors represent the 5-HT receptor subtypes identified mainly by radioligand binding main site of action of many drugs used for treating gastrointesti- and pharmacological studies (refs. 16, 17, and see Figure 1). nal motility disorders (Table 1) and are found widely distributed In terms of signal transduction and pharmacology, we now throughout the body (18). 5-HT6 and 5-HT7 receptors have recently know that all members of the 5-HT1 family are intronless and been the subject of intense investigation by pharmaceutical compa- couple to the Gi family of heterotrimeric G proteins — in keep- nies based on the discovery that many drugs ing with the original description of the 5-HT1A receptor (7). The have high affinities for both receptors (30). As can be seen in Table 1, compounds that target 5-HT6 and 5-HT7 receptors are currently in testing for depression, cognition enhancement, and psychosis. Conflict of interest: Herbert Y. Meltzer is a shareholder of ACADIA Pharmaceuticals and GlaxoSmithKline. He receives, or has received, grant or contract support from, or Drugs acting on 5-HT receptors display a range of from full is, or has been, a consultant to ACADIA, Alkermes, Astellas, BioLineRx, Bristol-Myers to inverse agonists (e.g., antagonists with negative intrin- Squibb, Dainippon Sumitomo Pharma, Eli Lilly, EnVivo Pharmaceuticals, Janssen sic activity). Buspiron, for instance, is a at 5-HT1A Pharmaceuticals Inc., , Otsuka, Pfizer, Sunovion, and Teva. Bryan L. Roth is a consultant to Pfizer and RuiYi and receives support from Dainippon Sumitomo receptors, whereas is a full agonist at 5-HT1D recep- Pharma. tors. By contrast, both typical and atypical antipsychotic drugs have Citation for this article: J Clin Invest. 2013;123(12):4986–4991. doi:10.1172/JCI70678. actions at many 5-HT receptor subtypes including

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Figure 1 Sites of action of 5-HT therapeutics. Shown in the middle is a table listing the major families of 5-HT receptors (viz. 5-HT1 to 5-HT7). As shown, the 5-HT1 family has five members (5-HT1A, 5-HT1B, 5-HT1D, 5-HT1E, and 5-HT1F), while the 5-HT2 family — the topic of this review — has three: 5-HT2A, 5-HT2B, and 5-HT2C. Each member of the 5-HT2 family displays distinct brain and tissue distributions. The 5-HT2A recep- tor is enriched in pyramidal neurons in layer V of the cerebral cortex, where it mediates the actions of pimavanserin and other atypical anti- psychotic drugs. The 5-HT2B receptor is enriched in interstitial cells of the heart valves, where it mediates the valvulopathic actions of certain drugs like . The 5-HT2C receptor is enriched in the hypo- , among other areas, particularly in nuclei engaged in regu- lating feeding behavior, where it mediates the actions of the appetite suppressant lorcaserin.

5-HT2A (31) and 5-HT2C (32). Inverse agonists represent drugs that Additionally, alterations in serotonergic neurotransmission have antagonize the action of full agonists (e.g., are “antagonists”) and been implicated in nearly every neuropsychiatric disorder, including simultaneously lower the basal level of receptor signaling (e.g., sup- and related psychotic disorders, major depression, press constitutive receptor activity; see ref. 33 for review). Essen- eating disorders, and so on (18). Many of the therapeutic actions, as tially, inverse agonists are antagonists with negative intrinsic activ- well as serious side effects of commonly prescribed medications, are ity. Finally, drugs like ergotamine display functional selectivity or due to nonspecific actions on 5-HT receptor subtypes (18, 27, 34). signaling bias for many 5-HT receptors including 5-HT2B (28, 29). Given this wealth of evidence implicating altered serotonergic neu- Thus, ergotamine has much higher for activating β-arrestin rotransmission in neuropsychiatric disease, as well as the plethora pathways than for activating G protein–mediated signaling (28, 29) of 5-HT receptor subtypes, it has long been proposed that drugs and as such is considered to display functional selectivity for β-ar- that target distinct 5-HT receptors might provide novel and effective restin signaling and to represent a β-arrestin–biased agonist. treatments for many neuropsychiatric disorders (Table 1). Because of the vast effort devoted over the past five decades to Despite the abundant evidence suggesting that selective sero- studying serotonin and classifying its receptors, we now appreci- tonergic drugs would prove efficacious for many diseases, a fun- ate that serotonin is involved in the regulation of nearly every CNS damental challenge encountered for creating them relates to the function, including cognition, autonomic function, perception, relatively similar binding pocket shared among 5-HT receptor sub- emotion, appetite, aggression, and mood, to name but a few (18). types. As seen in recent high-resolution structures derived from the

Table 1 Listed are approved/investigational drugs targeting distinct 5-HT receptor subtypes

Receptor subtype Known indications ( name) Potential new indications (medication name) References

5-HT1A Anxiety, depression Cognition enhancement 77 (buspirone) () 5-HT1B Migraine headaches Depression (AZD3783) 78 and 5-HT1D (sumatriptan, , , etc.) 5-HT1E Unknown NA 5-HT1F Migraine headaches NA 5-HT2A Hypertension () Psychosis (pimavanserin) This article 5-HT2B Pulmonary hypertension Fibrosis (NA) () 5-HT2C Obesity (lorcaserin) Psychosis, mood disorders, 18 anxiety, metabolic syndrome 5-HT3 -induced NA (odansetron, ,, etc.) 5-HT4 Gastrointestinal motility disorders Dementia (NA) 79 () 5-HT5 Unknown NA 5-HT6 NA Cognition enhancement in 80 Alzheimer’s disease, psychosis (SB-742457)

5-HT7 NA Depression, anxiety (NA) 81

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ably lower than that of valvular heart disease (41). We now know that both valvular heart disease (42) and pulmonary hypertension (43) are likely due to off-target interactions of fenfluramine’s principal metabolite with the 5-HT2B serotonin receptor (27). Thus, while the parent compound fenfluramine is relatively inactive at 5-HT2B receptors (42), norfenfluramine potently activates 5-HT2B receptors (42, 44). Indeed, the EC50 of norfenfluramine is approximately 80 nM for the activation of 5-HT2B receptors in vitro. This concentration is roughly equivalent to plasma levels of norfenfluramine in individuals taking fenflu- ramine for obesity (18). Thus, Arena Pharmaceuticals set out to create a 5-HT2C–selective agonist devoid of 5-HT2B agonist activity, predicting that such a molecule would be an effective agent devoid of cardiovascular side effects. Lorcaserin (also known as APD356) (Figure 2B and ref. 45) satisfied these criteria and was entered into clinical trials for the treatment of obesity. In 2010, the results from a large phase III were published (46), demonstrating that lorcaserin-treated indi- Figure 2 viduals (10 mg/day) achieved, on average, a 5.8-kg weight loss Structures of lorcaserin and pimavanserin in relationship to the sero- compared with a 2.2-kg weight loss in placebo-treated patients tonin receptor–binding pocket. Shown at the top are the structures of (P < 0.001) (Figure 3A). Both lorcaserin- and placebo-treated lorcaserin ((1R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benza- individuals were given diet and exercise guidance, with 47.5% zepine) and pimavanserin (N-(4-fluorophenylmethyl)-N-(1-methylpip- of lorcaserin-treated patients achieving ≥5% weight loss com- eridin-4-yl)-N′-(4-(2-methylpropyloxy)phenylmethyl)carbamide), and pared with 20.3% for those treated with placebo (Figure 3B). shown below is the consensus-binding pocket of 5-HT receptors. Importantly, there was no evidence for an increase in clinically significant valvular heart disease in lorcaserin-treated patients compared with those receiving placebo. Similar results were pharmacologically distinct 5-HT1B and 5-HT2B receptors (refs. 19, reported in a 1-year trial that examined two doses of lorcaserin 29, and Figure 2), many of the key amino acids essential for (10 or 20 mg/day); again, there was no difference in the inci- binding by the G protein–coupled 5-HT receptors are identical. dence of valvular heart disease in placebo- and lorcaserin-treated Until recently, this high degree of structural conservation made individuals (2.0% in both). In both trials, , nausea, and it challenging for medicinal chemists to create subtype-selective dizziness were among the most frequent side effects, and there 5-HT receptor–active drugs. As is evident from Table 1, and as has was no evidence for neuropsychiatric sequelae in either trial been briefly reviewed earlier, several selective serotonergic drugs (46, 47). Nasopharyngitis, sinusitis, and upper respiratory infec- have now survived the gauntlet of clinical trials and are approved tions were seen more commonly among lorcaserin-treated indi- for treating a number of diseases, including obesity, migraine viduals in one trial (46), but not in the other (47). Lorcaserin headaches, psychosis, anxiety, depression, chemotherapy-induced appears to achieve its weight-reducing effects by diminishing nausea, and even Alzheimer’s disease. caloric intake rather than by altering energy expenditure (48). In this review, we focus on one newly approved 5-HT2C–selective antiobesity medication (lorcaserin) and a 5-HT2A–selective inverse agonist with efficacy in the -dependent psychosis of Par- kinson’s disease (pimavanserin) that has recently been selected for expedited FDA review (see Figure 2 for structures). Currently, there is no approved treatment for this relatively common disorder. and , which are nonselective inverse agonists at the 5-HT2A receptor are rarely used because of unwanted side effects caused by their actions at other receptors (35).

Lorcaserin — a safe and effective antiobesity For many decades, it has been clear that 5-HT is a critically impor- tant neurotransmitter for the central regulation of appetite and metabolism (36) and that it is the 5-HT2C receptor that mediates the anorectic actions of 5-HT (37). The anorectic actions of the withdrawn antiobesity medication fenfluramine are due to the agonist actions of its metabolite norfenfluramine at 5-HT recep- Figure 3 tors (38). The combination of fenfluramine and the Lorcaserin induces significant weight loss. A( ) Average weight loss derivative was demonstrated to be a highly effective versus placebo with lorcaserin treatment (n = 1,538 in lorcaserin group appetite suppressant (39), but was withdrawn due an unacceptable vs. 1,499 in placebo group; P < 0.001). (B) Percentage of patients in rate of valvular heart disease (40). Fenfluramine was also linked each group who achieved ≥5% weight loss (P < 0.001 lorcaserin vs. to pulmonary hypertension, although the incidence was consider- placebo). Data republished with permission from ref. 46.

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Figure 4 Pimavanserin significantly improves delusions and hallucinations in PDP. Baseline and 28-day scale for the assessment of positive symp- toms (SAPS) of global delusions (A) and hallucinations (B) ratings for 30 patients per group with PDP treated with pimavanserin or placebo (P < 0.05), respectively. Data republished with permission from ref. 63.

Lorcaserin has also been evaluated in obese individuals with type 2 (4–6 ng/ml) in responsive PDP patients, it was concluded that clo- diabetes. In a pivotal study, O’Neill et al. found that lorcaserin zapine’s antagonist (or inverse agonist) activity at 5-HT2A receptors induced significant (P < 0.001) weight loss and improved glyce- was the basis for its efficacy (58). This provided further support mic control in individuals with type 2 diabetes compared with for the suggestion that selective 5-HT2A inverse agonists might be that observed in placebo-treated individuals (49). It must be noted useful as a monotherapy for some psychoses and to potentiate the that both groups received or sulfonylurea (or both), as antipsychotic action of subeffective doses of known APDs (24, 59). well as diet and exercise counseling. Thus, it cannot be concluded For these and other reasons, ACADIA Pharmaceuticals developed without further study that lorcaserin alone would be effective in selective 5-HT2A inverse agonists (31, 35). The compound ulti- producing weight loss in obese individuals with type 2 diabetes. As mately selected for clinical development was pimavanserin (60). Its in all other studies, serial echocardiograms were performed, and pKi (–log Ki) for the human 5-HT2A receptor is 9.3, with a 40-fold no significant (P > 0.05) drug effect was noted on the incidence of selectivity over the 5-HT2C receptors and little affinity for 5-HT2B valvular heart disease. Taken together, these results suggest that or D2 receptors (60). Pimavanserin demonstrated atypical antipsy- lorcaserin in combination with diet and exercise counseling can chotic-like activity in a variety of preclinical models (37, 38, 60). induce clinically significant weight loss and, perhaps, improve gly- It also reduced the release of DA in the nucleus accumbens from cemic control in obese individuals with type 2 diabetes. activated DA neurons (61), which may contribute to its antipsy- chotic effect, although direct effects on 5-HT2A receptors expressed Treating Parkinson’s disease psychosis: from clozapine on glutamatergic and GABAergic neurons may also contribute to to pimavanserin the actions of 5-HT2A inverse agonists (55, 62). It has long been held that all antipsychotic drugs (APDs) achieve Pimavanserin, 20–60 mg/day, was tested in a double-blind, their antipsychotic effect primarily through blockade of dopamine randomized, placebo-controlled, multicenter 28-day trial in (DA) D2 receptors (50); however, D2 receptor blockade also leads to 60 patients with L-DOPA–induced PDP (63). The pimavanser- deleterious extrapyramidal side effects (EPSs) and eleva- in-treated patients showed markedly greater improvement in delu- tion (51). At doses of 200 to 900 mg/day, clozapine was found to sions and hallucinations (Figure 4). Pimavanserin did not differen- produce antipsychotic action with minimal EPSs or prolactin ele- tiate from the placebo with regard to motor impairment, sedation, vation in patients with schizophrenia, an atypical profile compared , or other side effects (39, 63). These results were with other APDs (52, 53). Comparison of the affinities of typical recently confirmed in a 6-week, randomized, double-blind phase and atypical APDs for DA D1 and D2 and 5-HT2A receptors led to III study involving 198 patients, half of whom received pimavan- the hypothesis that one type of atypical APD could be identified by serin (64). The FDA subsequently indicated that it will evaluate a a higher affinity for 5-HT2A receptors than for D2 receptors (54). new drug application (NDA) from ACADIA on the basis of these Subsequently, a series of drugs that conformed to this hypothesis, two studies and other safety data (65). Preclinical studies indicate including , , and others, were developed for that pimavanserin may also be useful for treating the psychosis the treatment of schizophrenia (55). Unfortunately, other pharma- of Alzheimer’s disease (66). Pimavanserin has also been shown to cologic properties of these broadly acting drugs produced numer- potentiate a subeffective dose of the atypical APD risperidone in ous side effects that limited their tolerability (56), including 5-HT2C acutely psychotic patients with schizophrenia, producing a more inverse agonism, a major basis for metabolic side effects (57). rapid onset of action than standard-dose risperidone or an equally Typical APDs, even at ultra-low doses, cause intolerable motor effective dose of , while producing fewer side effects impairment in patients with Parkinson’s disease psychosis (PDP), (67). These results are consistent with evidence that pimavan- which is a common of L-DOPA and direct-acting DA serin, as well as other 5-HT2A inverse agonists, is able to potentiate agonists. By contrast, clozapine, at doses of 12.5 to 75 mg/day, was subeffective doses of atypical, but not typical, APDs in clinically found to be an effective and tolerable treatment for PDP (35); how- relevant animal models of psychosis and cognitive impairment ever, serious, nonmotoric side effects of clozapine limit its use in (68, 69). The possibility that pimavanserin is effective as a mono- PDP (30, 35). After an examination of plasma levels of clozapine therapy for some patients with schizophrenia is consistent with

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the finding that SR43469B, another 5-HT2A inverse agonist, was both as monotherapy and adjunctive treatment. One thing that reported to diminish psychotic symptoms more effectively than is unclear, however, is the degree of inverse agonism required for placebo, but slightly less so than haloperidol, in acutely psychotic therapeutic efficacy in psychosis and related disorders (76), and patients with schizophrenia (59). future studies examining drugs with a range of antagonist func- tional selectivity and inverse agonism will be needed to address Conclusions this point. Finally, additional extensive research is needed to estab- The approval of lorcaserin by the FDA in June 2012 marks the cul- lish the range of disorders in which 5-HT2A inverse agonists can mination of many years of basic science investigation in fields as substitute for or augment subeffective doses of APDs. At least for disparate as the central control of appetite and drug-induced val- PDP, pimavanserin may be considered a potential next-generation vular heart disease. Thus, the pivotal discoveries that 5-HT2C recep- atypical APD. tors are essential mediators of both appetite (37) and the anorectic Taken together, these findings underscore the importance of actions of fenfluramine (38) and that the closely related receptor an in-depth understanding of the biology and pharmacology of 5-HT2B is responsible for drug-induced valvular heart disease specific subtypes of 5-HT receptors and how this may lead to the (27, 42) paved the way for the design of novel serotonergic drugs development of novel treatments with selective clinical predicted to be effective in reducing appetite without cardiovas- and fewer side effects compared with prior medications. cular side effects. Additionally, since it is now well established that drugs can selectively engage either G protein or β-arrestin signal- Acknowledgments ing (70, 71), drugs with selective signaling bias for one pathway All primary research reported here from Bryan L. Roth’s laboratory over another may have distinct clinical advantages over drugs was supported by NIH grants (RO1MH61887, U19MH82441, and without functional selectivity (72–75). It will be important to NIMH Screening Program). determine whether 5-HT2C agonists with signaling bias represent a therapeutic advance over drugs without functional selectivity. Address correspondence to: Bryan L. Roth, Department of Phar- The clinical studies cited here (58) are consistent with preclini- macology, University of North Carolina Chapel Hill Medical cal data demonstrating that selective 5-HT2A inverse agonism is a School, CB#7635, Chapel Hill, North Carolina 27514, USA. Phone: valuable mechanism for treating psychosis with fewer side effects, 919.966.7535; Fax: 919.843.5788; E-mail: [email protected].

1. Rapport MM, Green AA, Page IH. Crystalline sero- 3H-ligand for serotonin2 receptor binding sites. versus magic bullets: selectively non-selective drugs tonin. Science. 1948;108(2804):329–330. Mol Pharmacol. 1982;21(2):301–314. for mood disorders and schizophrenia. Nat Rev 2. Wooley DW, Shaw E. A biochemical and pharmaco- 14. Conn PJ, Sanders-Bush E, Hoffman BJ, Hartig PR. Drug Discov. 2004;3(4):353–359. logical suggestion about certain mental disorders. A unique serotonin receptor in choroid plexus is 25. Roth BL, Willins DL, Kristiansen K, Kroeze Proc Natl Acad Sci U S A. 1954;40(4):228–231. linked to phosphatidylinositol turnover. Proc Natl WK. 5-Hydroxytryptamine2-family receptors 3. Gaddum JH, Picarelli ZP. Two kinds of trypt- Acad Sci U S A. 1986;83(11):4086–4088. (5-hydroxytryptamine2A, 5-hydroxytryptamine2B, amine receptors. Br J Pharmacol Chemother. 1957; 15. Pazos A, Hoyer D, Palacios JM. The binding of 5-hydroxytryptamine2C): where structure meets 12(3):323–328. serotonergic ligands to the procine choroid plexus: function. Pharmacol Ther. 1998;79(3):231–257. 4. Dixon RA, et al. Cloning of the gene and cDNA for characterization of a new type of serotonin recog- 26. Roth B, Willins D, Kristiansen K, Kroeze W. Acti- mammalian beta- and homol- nition site. Eur J Pharmacol. 1984;106(3):539–546. vation is hallucinogenic and antagonism is ther- ogy with rhodopsin. Nature. 1986;321(6065):75–79. 16. Dumuis A, Sebben M, Bockaert J. The gastrointesti- apeutic: role of 5-HT2A receptors in atypical anti- 5. Gozlan H, El Mestikawy S, Pichat L, Glowinski J, nal prokinetic derivatives are agonists at psychotic drug actions. The Neuroscientist. 1999; Hamon M. Identification of presynaptic serotonin the non-classical 5-HT receptor (5-HT4) positively 5:254–262. autoreceptors using a new ligand: 3H-PAT. Nature. coupled to adenylate cyclase in neurons. Naunyn 27. Roth BL. Drugs and valvular heart disease. N Engl J 1983;305(5930):140–142. Schmiedebergs Arch Pharmacol. 1989;340(4):403–410. Med. 2007;356(1):6–9. 6. Kobilka FK, et al. An intron-less gene encoding a 17. Bockaert J, Sebben M, Dumuis A. Pharmacological 28. Huang XP, et al. Parallel functional activity profil- potential member of the family of receptors cou- characterization of 5-hydroxytryptamine4(5-HT4) ing reveals valvulopathogens are potent 5-hydroxy- pled to guanine nucleotide regulatory proteins. receptors positively coupled to adenylate cyclase in tryptamine(2B) receptor agonists: implications Nature. 1987;329(6134):75–79. adult guinea pig hippocampal membranes: effect of for drug safety assessment. Mol Pharmacol. 2009; 7. Fargin A, Raymond JR, Lohse MJ, Kobilka BK, substituted benzamide derivatives. Mol Pharmacol. 76(4):710–722. Caron MG, Lefkowitz RJ. The genomic clone G-21 1990;37(3):408–411. 29. Wacker D, et al. Structural features for functional which resembles a β-adrenergic receptor sequence 18. Berger M, Gray JA, Roth BL. The expanded biology selectivity at serotonin receptors. Science. 2013; encodes the 5-HT1A receptor. Nature. 1988; of serotonin. Annu Rev Med. 2009;60:355–366. 340(6132):615–619. 335(6188):358–360. 19. Wang C, et al. Structural basis for molecular rec- 30. Roth BL, et al. Binding of typical and atypical anti- 8. Kroeze WK, Roth BL. The molecular biology of sero- ognition at serotonin receptors. Science. 2013; psychotic agents to 5- hydroxytryptamine-6 and tonin receptors: therapeutic implications for the 340(6132):610–614. 5-hydroxytryptamine-7 receptors. J Pharmacol Exp interface of mood and psychosis. Biol Psychiatry. 1998; 20. Roth BL, Nakaki T, Chuang DM, Costa E. Aortic Ther. 1994;268(3):1403–1410. 44(11):1128–1142. recognition sites for serotonin (5HT) are coupled 31. Weiner DM, et al. 5-hydroxytryptamine2A receptor 9. Kroeze WK, Kristiansen K, Roth BL. Molecular biol- to phospholipase C and modulate phosphati- inverse agonists as . J Pharmacol Exp ogy of serotonin receptors structure and function dylinositol turnover. Neuropharmacology. 1984; Ther. 2001;299(1):268–276. at the molecular level. Curr Top Med Chem. 2002; 23(10):1223–1225. 32. Rauser L, Savage JE, Meltzer HY, Roth BL. Inverse 2(6):507–528. 21. Conn PJ, Sanders-Bush E. Selective 5-HT2 agonist actions of typical and atypical antipsy- 10. Middlemiss DN. Stereoselective blockade at antagonists inhibit serotonin-stimulated phos- chotic drugs at the human 5-hydroxytryptam- [3H]5-HT binding sites and at the 5-HT auto- phatidylinositol metabolism in cerebral cortex. ine(2C) receptor. J Pharmacol Exp Ther. 2001; receptor by . Eur J Pharmacol. 1984; Neuropharmacology. 1984;23(8):993–996. 299(1):83–89. 101(3–4):289–293. 22. Roth BL, Nakaki T, Chuang DM, Costa E. 33. Kenakin T. Drug efficacy at G protein-coupled recep- 11. Leonhardt S, Herrick-Davis K, Titeler M. Detection 5-Hydroxytryptamine2 receptors coupled to tors. Annu Rev Pharmacol Toxicol. 2002;42:349–379. of a novel serotonin receptor subtype (5-HT1E) in phospholipase C in rat aorta: modulation of phos- 34. Keiser MJ, et al. Predicting new molecular targets human brain: interaction with a GTP-binding pro- phoinositide turnover by phorbol ester. J Pharmacol for known drugs. Nature. 2009;462(7270):175–181. tein. J Neurochem. 1989;53(2):465–471. Exp Ther. 1986;238(2):480–485. 35. Starkstein SE, Brockman S, Hayhow BD. Psychi- 12. Leysen JE, Niemegeers CJ, Tollenaere JP, Laduron 23. Roth BL, Ciaranello RD, Meltzer HY. Binding of typ- atric syndromes in Parkinson’s disease. Curr Opin PM. Serotonergic component of neuroleptic recep- ical and atypical antipsychotic agents to transiently Psychiatry. 2012;25(6):468–472. tors. Nature. 1978;272(5649):168–171. expressed 5-HT1C receptors. J Pharmacol Exp Ther. 36. Blundell JE. Serotonin and appetite. Neuropharma- 13. Leysen JE, Niemegeers CJE, Van Nueten JM, 1992;260(3):1361–1365. cology. 1984;23(12B):1537–1551. Laduron PM. [3H]-ketanserin (R 41 468) a selective 24. Roth BL, Sheffler DJ, Kroeze WK. Magic shotguns 37. Tecott LH, et al. Eating disorder and epilepsy in mice

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lacking 5-HT2c serotonin receptors. Nature. 1995; choses. 2012;6(3):134–144. not enhance efficacy of haloperidol, 2mg/day: com- 374(6522):542–546. 54. Meltzer HY, Matsubara S, Lee J-C. Classification parison with reference dose risperidone, 6mg/day. 38. Vickers SP, Clifton PG, Dourish CT, Tecott LH. of typical and atypical antipsychotic drugs on the Schizophr Res. 2012;141(2–3):144–152. Reduced satiating effect of d-fenfluramine in sero- basis of dopamine D-1, D-2 and serotonin2 pKi val- 68. Gardell LR, et al. ACP-103, a 5-hydroxytryptamine tonin 5-HT(2C) receptor mutant mice. Psychophar- ues. J Pharmacol Exp Ther. 1989;251(1):238–246. 2A receptor inverse agonist, improves the antipsy- macology (Berl). 1999;143(3):309–314. 55. Meltzer HY, Huang M. In vivo actions of atypical chotic efficacy and side-effect profile of haloperi- 39. Weintraub M, Hasday JD, Mushlin AI, Lock- antipsychotic drug on serotonergic and dopamin- dol and risperidone in experimental models. J Phar- wood DH. A double-blind clinical trial in weight ergic systems. Prog Brain Res. 2008;172:177–197. macol Exp Ther. 2007;322(2):862–870. control. Use of fenfluramine and phentermine 56. Meltzer HY. Update on typical and atypical antipsy- 69. Snigdha S, et al. Attenuation of -in- alone and in combination. Arch Intern Med. 1984; chotic drugs. Annu Rev Med. 2013;64:393–406. duced object recognition deficits by the combi- 144(6):1143–1148. 57. Kroeze WK, et al. H1- receptor affinity nation of atypical antipsychotic drugs and pima- 40. Connolly HM, et al. Valvular heart disease associated predicts short-term weight gain for typical and atyp- vanserin (ACP 103), a 5-hydroxytryptamine(2A) with fenfluramine-phentermine. N Engl J Med. 1997; ical antipsychotic drugs. Neuropsychopharmacology. receptor inverse agonist. J Pharmacol Exp Ther. 2009; 337(9):581–588. 2003;28(3):519–526. 332(2):622–631. 41. Brenot F, Herve P, Petitpretz P, Parent F, Duroux P, 58. Meltzer HY, Kennedy J, Dai J, Parsa M, Riley D. 70. Luttrell LM, et al. Beta-arrestin-dependent forma- Simonneau G. Primary pulmonary hypertension and Plasma clozapine levels and the treatment of tion of beta2 adrenergic receptor-Src protein kinase fenfluramine use. Br Heart J. 1993;70(6):537–541. L-DOPA-induced psychosis in Parkinson’s disease. complexes. Science. 1999;283(5402):655–661. 42. Rothman RB, et al. Evidence for possible involve- A high potency effect of clozapine. Neuropsychophar- 71. Beaulieu JM, et al. A β-arrestin 2 signaling complex ment of 5-HT(2B) receptors in the cardiac val- macology. 1995;12(1):39–45. mediates action on behavior. Cell. 2008; vulopathy associated with fenfluramine and 59. Meltzer HY, Arvanitis L, Bauer D, Rein W. Placebo- 132(1):125–136. other serotonergic medications. Circulation. 2000; controlled evaluation of four novel compounds for 72. Noma T, et al. Beta-arrestin-mediated beta1-ad- 102(23):2836–2841. the treatment of schizophrenia and schizoaffective renergic receptor transactivation of the EGFR 43. Launay JM, et al. Function of the serotonin disorder. Am J Psychiatry. 2004;161(6):975–984. confers cardioprotection. J Clin Invest. 2007; 5-hydroxytryptamine 2B receptor in pulmonary 60. Vanover KE, et al. Pharmacological and behavioral 117(9):2445–2458. hypertension. Nat Med. 2002;8(10):1129–1135. profile of N-(4-fluorophenylmethyl)-N-(1-meth- 73. Walters RW, et al. β-Arrestin1 mediates nic- 44. Fitzgerald LW, et al. Possible role of valvular sero- ylpiperidin-4-yl)-N′-(4-(2-methylpropyloxy)phen otinic acid-induced flushing, but not its tonin 5-HT(2B) receptors in the cardiopathy asso- ylmethyl) carbamide (2R,3R)-dihydroxybutane- antilipolytic effect, in mice. J Clin Invest. 2009; ciated with fenfluramine. Mol Pharmacol. 2000; dioate (2:1) (ACP-103), a novel 5-hydroxytryptam- 119(5):1312–1321. 57(1):75–81. ine(2A) receptor inverse agonist. J Pharmacol Exp 74. Allen JA, et al. Discovery of β-arrestin-biased dopa- 45. Thomsen WJ, et al. Lorcaserin, a novel selective Ther. 2006;317(2):910–918. mine D2 ligands for probing signal transduction human 5-hydroxytryptamine2C agonist: in vitro 61. Li Z, Ichikawa J, Huang M, Prus AJ, Dai J, Meltzer pathways essential for antipsychotic efficacy. Proc and in vivo pharmacological characterization. HY. ACP-103, a 5-HT2A/2C inverse agonist, poten- Natl Acad Sci U S A. 2011;108(45):18488–18493. J Pharmacol Exp Ther. 2008;325(2):577–587. tiates haloperidol-induced dopamine release in rat 75. Allen JA, Roth BL. Strategies to discover unexpected 46. Smith SR, et al. Multicenter, placebo-controlled medial prefrontal cortex and nucleus accumbens. targets for drugs active at g protein-coupled recep- trial of lorcaserin for weight management. N Engl Psychopharmacology (Berl). 2005;183(2):144–153. tors. Annu Rev Pharmacol Toxicol. 2011;51:117–144. J Med. 2010;363(3):245–256. 62. Fribourg M, et al. Decoding the signaling of a GPCR 76. Yadav PN, Kroeze WK, Farrell MS, Roth BL. 47. Fidler MC, et al. A one-year randomized trial of heteromeric complex reveals a unifying mecha- Antagonist functional selectivity: 5-HT2A sero- lorcaserin for weight loss in obese and overweight nism of action of antipsychotic drugs. Cell. 2011; tonin receptor antagonists differentially regulate adults: the BLOSSOM trial. J Clin Endocrinol Metab. 147(5):1011–1023. 5-HT2A receptor protein level in vivo. J Pharmacol 2011;96(10):3067–3077. 63. Meltzer HY, et al. Pimavanserin, a serotonin(2A) Exp Ther. 2011;339(1):99–105. 48. Martin CK, et al. Lorcaserin, a 5-HT(2C) receptor receptor inverse agonist, for the treatment of Parkin- 77. Sumiyoshi T, et al. Enhancement of cognitive per- agonist, reduces body weight by decreasing energy son’s disease psychosis. Neuropsychopharmacology. formance in schizophrenia by addition of tandos- intake without influencing energy expenditure. 2010;35(4):881–892. pirone to neuroleptic treatment. Am J Psychiatry. J Clin Endocrinol Metab. 2010;96(3):837–845. 64. Cummings JL, et al. Antipsychotic efficacy 2001;158(10):1722–1725. 49. O’Neil PM, et al. Randomized placebo-controlled and motor tolerability in a Phase III placebo 78. Zhang M, et al. Preclinical pharmacology and phar- clinical trial of lorcaserin for weight loss in type 2 controlled study of pimavansserin in patients macokinetics of AZD3783, a selective 5-hydroxy- diabetes mellitus: the BLOOM-DM study. Obesity with Parkinson’s disease psychosis. Neurology. tryptamine 1B . J Pharmacol Exp (Silver Spring). 2012;20(7):1426–1436. 2013;80(19):e530. Ther. 2011;339(2):567–578. 50. Kapur S, Seeman P. Does fast dissociation from 65. ACADIA Pharmaceuticals, Inc. Web Site. Pima- 79. Brodney MA, et al. Identification of multiple the dopamine d(2) receptor explain the action of vanserin overview. http://www.acadia-pharm. 5-HT(4) partial agonist clinical candidates for the atypical antipsychotics?: A new hypothesis. Am J com/pipeline/pimavanserin.htm. Accessed treatment of Alzheimer’s disease. J Med Chem. 2012; Psychiatry. 2001;158(3):360–369. October 30, 2013. 55(21):9240–9254. 51. Meltzer HY, Stahl SM. The dopamine hypothesis 66. Price DL, Bonhaus DW, McFarland K. Pimavan- 80. Maher-Edwards G, et al. Double-blind, controlled of schizophrenia: a review. Schizophr Bull. 1976; serin, a 5-HT2A receptor inverse agonist, reverses phase II study of a 5-HT6 receptor antagonist, 2(1):19–76. psychosis-like behaviors in a rodent model of SB-742457, in Alzheimer’s disease. Curr Alzheimer 52. Angst J, Bemte D, Berner P, Heimann H, Helmchen Alzheimer’s disease. Behav Pharmacol. 2012; Res. 2010;7(5):374–385. H, Hippius H. Das klinische wirkungsbild von clo- 23(4):426–433. 81. Abbas AI, Hedlund PB, Huang XP, Tran TB, Meltzer zapine. Pharmacopsychiaties. 1971;4:201–221. 67. Meltzer HY, et al. Pimavanserin, a selective seroto- HY, Roth BL. is a potent 5-HT7 antag- 53. Meltzer HY. Clozapine: balancing safety with supe- nin (5-HT)2A-inverse agonist, enhances the effi- onist: relevance for actions in vivo. rior antipsychotic efficacy. Clin Schizophr Relat Psy- cacy and safety of risperidone, 2mg/day, but does Psychopharmacology (Berl). 2009;205(1):119–128.

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